2-Phenyl-4-quinolinecarboxylic acids are disclosed as tumor-inhibiting agents by U.S. Pat. No. 4,680,299, issued to Hesson on Jul. 14, 1987. Utility of these compounds for the treatment of skin and epithelial diseases is disclosed by U.S. Pat. No. 4,861,783, issued to Ackerman et al. on Aug. 29, 1989. Utility of these compounds as immunomodulatory or immunosuppressive agents is disclosed by U.S. Pat. No. 4,968,701, issued to Ackerman et al. on Nov. 6, 1990. U.S. Pat. No. 5,204,329, issued to Ackerman et al. on Apr. 20, 1993, describes the use of these compounds in combination with a second immunosuppressive agent for the treatment of transplantation rejection and other disease conditions.
Additional examples of 2-phenyl-4-quinolinecarboxylic acids are disclosed as useful in the treatment of arthritis and for inducing immunosuppression in U.S. Pat. No. 4,847,381, issued to Sutherland et al. on Jul. 11, 1989; and in U.S. Pat. No. 4,968,702, issued to Poletto et al. on Nov. 6, 1990.
Benz[c]acridine-7-carboxylic acids and 5,6-dihydrobenz[c]acridine-7-carboxylic acids are known in the chemical literature. They are generally synthesized by the Pfitzinger reaction of an appropriate isatin with an appropriate 3,4-dihydro-1(2H)-naphthalenone. U.S. Pat. No. 4,918,077, issued to Behrens on Apr. 17, 1990, discusses a number of references dealing with these compounds, and also discloses tumor-inhibiting 3-phenyl-5,6-dihydrobenz[c]acridine-7-carboxylic acids of the formula: ##STR1## where R.sup.1 is, inter alia, COOH, COONa or COOK; R.sup.2 and R.sup.3 are independently H, F, Cl, Br, I, methyl, ethyl, CF.sub.3, alkylthio, alkylsulfinyl, or alkylsulfonyl; and R.sup.4 and R.sup.5 independently are H or taken together are S. U.S. Pat. No. 5,135,934, issued to Behrens et al. on Aug. 4, 1992, discloses the utility of these compounds as immunosuppressive and anti-inflammatory agents.
The synthesis of ring-fused quinolinecarboxylic acids of the formula: ##STR2## where n is 1-4, and R is H or methyl, has also been reported by Huisgen et al. [Ann. Chem. (1957) 610:57] and Schoen et al. [Rocz. Chem. (1964) 38:425; Chem. Abstr. 61, 1827g]. Noelting et al. [Chem. Ber. (1911) 44:2585] reported the synthesis of these compounds also, as well as of the compound where R is H and where (CH.sub.2).sub.n has been replaced by S. The same compound, but where R is methyl and (CH.sub.2).sub.n is replaced by S, was synthesized by Buu-Hoi [J. Chem. Soc. C (1966) 47] as an intermediate to potential carcinogens.
The synthesis of 4,5-dihydrofuro[2,3-c]acridine-6-carboxylic acids of the formula: ##STR3## where R is methyl, phenyl, or 4-bromophenyl, has been reported by Takagi et al. [Chem. Pharm. Bull. (1971) 19:1218, and Chem. Pharm. Bull. (1972) 20:2051].
Buu-Hoi et al. [J. Chem. Soc. (1958) 2418] reported the synthesis of the compound shown below as an intermediate for potential carcinogens. ##STR4##
Cagniant et al. [Bull. Soc. Chim. Fr. (1969) 991, and Bull. Soc. Chim. Fr. (1970) 322] reported the synthesis of other thienoacridine analogs of the formula: ##STR5## where R is H or methyl and n is 1 or 2.
The compound shown below was reported by Braunholtz et al. [J. Chem. Soc. (1962) 4346] as a synthetic intermediate. ##STR6##
Benzofuro[3,2-b]quinolines of the formula: ##STR7## where R is lower alkyl or carboxy are disclosed in Jpn. Kokai Tokkyo Koho 63,295,579, issued to Kinoshita et al. on Dec. 1, 1988 [Chem. Abstr. 111, 187618], with utility in the treatment of osteoporosis. Analogous carboxylic acids substituted with a single halogen atom, as well as the corresponding N-oxides, were synthesized by Yamaguchi et al. [J. Heterocyclic Chem. (1989) 26:285] as intermediates to potential carcinogens, mutagens and antitumor substances. An additional compound of the same formula, where R is COOH, where a methoxy substituent is present on the benzofuran ring, and where the O has been replaced by S, has also been synthesized by Buu-Hoi et al. [Israel J. Chem. (1963) 1:369; Chem. Abstr. 60, 11998f].
Degutis et al. [Khim. Geterotsikl. Soedin. (1986) 1375; Chem. Abstr. 107, 39658] and Ezerskaite et al. [Izv. Khim. (1989) 22:113; Chem. Abstr. 112, 66492, and Izv. Khim. (1989) 22:232; Chem. Abstr. 113, 58979] synthesized indoloquinoline carboxylic acids of the formula: ##STR8## where R.sup.1 and R.sup.2 are H or alkyl and R.sup.3 is H or bromo, and disclosed utility as sensitizers for electrophotography. Holt et al. [J. Chem. Soc. (1947) 607] also discuss the synthesis of this type of compound.
Fravolini et al. [Ann. Chim. (1968) 58:1155; Chem. Abstr. 70, 47334] synthesized the fluorinated benzothiopyranoquinoline carboxylic acids shown below. ##STR9##
Hou et al. [Youji Huaxue (1991) 11:615; Chem. Abstr. 116, 128709] reported the synthesis of the compounds shown below, where R is H or halogen. ##STR10##
Wang et al. [Gaodeng Xuexiao Huaxue Xuebao (1991) 12:59; Chem. Abstr. 115, 49457, and Zhongguo Yiyao Gongye Zashi (1991) 22:103; Chem. Abstr. 115:183138] disclosed the synthesis and anti-inflammatory activity of 7-carboxyisochromano[4,3-b]quinolines of the formula: ##STR11## where R is H, halogen or methyl. A compound of this formula, but lacking the R group and with O replaced by S, was synthesized by Braun et al. [Chem. Ber. (1929) 62:2416] and by Kiang et al. [J. Chem. Soc. (1951) 1909]. No utility was reported for this latter compound.
Roussel et al. [J. Chem. Soc. (1965) 5458] reported the synthesis of dibenzonaphthyridine derivatives of the formula: ##STR12## where R.sup.1 is H, methyl or chloro; R.sup.2 is H, methoxy or chloro, and R.sup.3 is H or methyl, as potential carcinogens.
The quinolinonaphthyridine derivatives show below (R=H, acetyl) were reported by Settimo et al. [J. Heterocyclic Chem. (1979) 16:169]. ##STR13##
Synthesis of similar compounds, lacking the methyl substituent shown above but where R is methyl or phenyl, have been reported by Braunholtz et al. [J. Chem. Soc. (1955) 381] and Mann [J. Chem. Soc. (1949) 2816], respectively.
The benzoquinolinoazepine derivatives of the formula: ##STR14## where R is methyl or tosyl have been synthesized by Braunholtz et al. [J. Chem. Soc. (1958) 3377] and by Proctor et al. [J. Chem. Soc. Perkin Trans. I (1978) 862], respectively. Another compound of this formula, but with NR replaced by S, was synthesized by Huckle et al. [J. Chem. Soc. C (1971) 2252].
There are no literature references disclosing the ring-fused quinolinecarboxylic acids or derivatives thereof of the present invention, or their use in treating and/or preventing immunologic disorders.
Presently, cyclosporin A, an immunosuppressive agent, used in combination with other adjunctive therapies, such as azathioprine and corticosteroids, is the treatment of choice for the prevention of organ transplantation rejection. Other immunosuppressive agents such as azathioprine, corticosteroids (such as prednisone), OKT3, FK506, mycophenolic acid or the 2-(N-morpholino)ethyl ester thereof, 15-deoxyspergualin, rapamycin, mizoribine, misoprostol and anti-interleukin-2 receptor antibodies, have been used or have been suggested to be useful in the treatment and/or prevention of organ transplantation rejection.
Use of any of these known immunosuppressive compounds, either alone or in combination, is associated with a high incidence of side effects such as nephrotoxicity and/or hepatoxicity. Thus, there presently exists a need for improved therapies for the treatment of cancer and for the treatment and/or prevention of organ transplantation rejection, graft versus host disease, autoimmune diseases, and chronic inflammatory diseases, including but not limited to psoriasis and rheumatoid arthritis.
It has now been found that the carbocyclic and heterocyclic fused-ring quinolinecarboxylic acid compounds described herein are useful for the treatment and/or prevention of organ transplantation rejection, graft versus host disease, autoimmune diseases, and chronic inflammatory diseases, including but not limited to psoriasis and rheumatoid arthritis, in a mammal.
The carbocyclic and heterocyclic fused-ring quinolinecarboxylic acid compounds of this invention can be used alone or in combination with one or more additional known immunosuppressive agents, such as cyclosporin A (CSA or CsA) and analogs thereof, FK506 (or FK-506) and analogs thereof, corticosteroids, azathioprine (AZA), mycophenolic acid or the 2-(N-morpholino)ethyl ester thereof, mycophenolate mofetil, rapamycin, 15-deoxyspergualin, mizoribine, leflunomide, OKT3, anti-interleukin-2 receptor antibodies, misoprostol, methotrexate, cyclophosphamide, and anti-lymphocyte/thymocyte serums, thereby to reduce the dosage required and associated adverse effects of these immunosuppressive agents.